Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
The invention pertains to the use of compounds represented by the formula, Q-G 1 -G 2 -G 3 -G 4 -Z, where Q is The compounds can be used as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.
1. A compound of Formula (I), pharmaceutically acceptable salts or stereoisomers thereof,
Q-G 1 -G 2 -G 3 -G 4 -Z Formula (I)
wherein Q is
wherein R 6 is an optionally substituted aryl or optionally substituted heteroaryl group, wherein the optional substituents are one or more groups selected from a group H, (C 1 -C 4 )alkyl, halo, halo(C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, —C(O) x R a , —OR a —S(O) x R a , —NR a R b , —C(O)NR a R b , —NR a C(O)R b , —NR a CO NR a R b , —S(O) 2 NR a R b or —NR a S(O) 2 NR a R b where x is an integer of 1 or 2; and
T is N, CH or CMe;
G 1 and G 3 are independently selected from the group consisting of cyclo(C 3 -C 8 )alkylene, heterocyclo(C 3 -C 8 )alkylene, arylene and heteroarylene, optionally substituted with one or two groups independently selected from halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 4 )perfluoroalkyl; —N(R a R b ), —N(R a )—C(O)(R a ), —C(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —S(O) 2 (R b ), —C(O)(R a ), wherein R a and R b are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl and aryl(C 1 -C 4 )alkyl;
G 2 is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O, N(R a )C(O), S and S(O) 2 , wherein R a is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl and aryl(C 1 - C 4 )alkyl;
G 4 is X—Y—;
wherein X is selected from null, O, NH, CO, CHOH, S or S(O) 2 ; and Y is selected from (C 1 -C 4 )alkylene, C 3 -C 8 -cycloalkylene or heterocycloalkylene, —CH(R 9 )C(R 10 R 11 )— or —N(R 9 )C(R 10 R 11 )—;
wherein:
R 10 and R 11 are both hydrogen, and R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, phenoxy-(C 2 -C 6 )alkyl, 1-methyl-1H-indol-3-yl, bis[(C 1 -C 6 )alkyl]amino-(C 2 -C 6 )alkyl, 1-piperidinyl-(C 2 -C 6 )alkyl, 1-pyrrolidinyl-(C 2 -C 6 )alkyl, or 1-morpholinyl-(C 2 -C 6 ) alkyl; or R 10 and R 11 are both hydrogen and R 9 is R 12 (CH 2 ) m , where m is 0 to 3, and R 12 is phenyl optionally substituted with one or more halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl or cyano; or
R 10 and R 11 are both hydrogen and R 9 is R 12 (CH 2 ) m , where m is 0 to 3, and R 12 is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, each of which is optionally substituted with halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl or cyano; or
R 9 is hydrogen, and R 10 and R 11 together with the carbon atom to which they are attached, form a three to five-membered ring, with 0 to 2 heteroatoms independently selected from O, S or N; or
R 10 is hydrogen, and R 9 and R 11 together with the two carbon atoms to which they are attached, form a three- to six-membered ring with 0 to 2 heteroatoms independently selected from O, S or N;
Z is
X 1 and X 2 are independently selected from null, (C(R a R b )) n , O, NR a , S or CO and n is 0 or 1; W is selected from H, (C 1 -C 6 )alkyl, aryl, heteroaryl or (C 3 -C 8 )cycloalkyl; wherein each of the (C 1 -C 6 )alkyl, aryl, heteroaryl and cycloalkyl is independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, —OR a , —O—C(O)(R a ), —S(R a ), —S(O)(R b ), —S(O) 2 (R b ), —C(O)(R a ), —C(O)(OR a ), —N(R a ) 2 , —N(R a )—C(O)(R a ), —C(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —(CR a R b ) t OR a , —(CR a R b ) t —O—C(O)(R a ), —(CR a R b ) t S(R a ), —(CR a R b ) t S(O)(R b ), —(CR a R b ) t S(O) 2 (R b ), —(CR a R a ) t C(O)(R a ), —(CR a R b ) t C(O)(OR a ), —(CR a R b ) t N(R a R b ) —(CR a R b ) t N(R a )—C(O)(R a ), —(CR a R b ) t C(O)N(R a ) 2 , —(CR a R a ) t S(O) 2 N(R a ) 2 and —(CR a R b ) t R a , —(CR a R b ) t P(O)(OH) 2 , and —(CR a R b ) t P(O)(OH)(R a ), wherein t is an integer of 1, 2, 3, or 4 and R a and R b are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl and aryl(C 1 -C 4 )alkyl; X 1 and X 2 may be combined to form a 5-, 6- or 7-membered ring having from 0 to 3 heteroatoms selected from the group consisting of NR a , O and S; or X 1 or X 2 may be combined with W to form a 5-, 6-or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of NR a , O and S; and
with a proviso that when X 2 is O, then X 1 is not (C(R a R b )) n .
2. The compound according to claim 1 , wherein said compound is:
Compound Number
Structure
5
3. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier, vehicle or diluent and a compound according to claim 1 .
4. The composition according to claim 3 , wherein said compound is:
Compound Number
Structure
5